Cafestol-derivatives as potential FXR agonists and CYP7A1 inhibitors and their impact on hypercholesterolemia: an in silico study

Cafestol is a hypercholesterolemic ent-kaurane diterpene found in unfiltered coffee, a regular component of the human diet. This diterpene is reported to modulate macromolecules involved in cholesterol metabolism, such as the farnesoid X receptor (FXR) and the cytochrome P450 7A1 enzyme (CYP7A1) in both in vitro and in vivo models. However, there are no studies on the hypercholesterolemic potential of cafestol roasting derivatives and phase I metabolites of cafestol, which share the same ent-kaurane scaffolds. In the present work, we compared binding modes of cafestol roasting derivatives and phase I metabolites of cafestol identified in a zebrafish model with two human protein-targets, FXR and CYP7A1, using molecular docking and molecular dynamics simulations (MDS) guided by cavity detection studies. We also performed a pharmacophore map focusing on the steroidal skeleton of co-crystallized ligands of these two protein targets and compared it with the ent-kaurane nucleus, along with an in silico ADME analysis of cafestol roasting derivatives to predict their physicochemical and pharmacokinetic properties. Based on their structural similarity to cafestol, this study preliminarily supports that these compounds may contribute to increased serum cholesterol, through interaction with these targets, thereby intensifying the cardiovascular risk associated with the consumption of unfiltered coffee beverages.